This is a renewal application for the Midwest Sexually Transmitted Diseases Cooperative Research Center (STDCRC). It is a consortium agreement between Indiana University and Northwestern University Schools of Medicine. The primary objective of this Center is to focus the efforts of investigators with different scientific backgrounds and interests on sexually transmitted diseases in such a way as to lead to new approaches to primary and secondary prevention. Specifically, it is our intention to foster productive, interdisciplinary collaboration in such a way as to enhance the capabilities of individual investigators and to stimulate the entry of other talented investigators into the field. The projects proposed include two focused on diseases associated with genital ulcers, herpes simplex virus and Haemophilus ducreyi infection. The first of these will evaluate molecular mechanisms associated with infectivity and dissemination in a mouse model; while the second will standardize a human challenge model and use it to evaluate the cellular immune response to H. ducreyi. A third project is directed at understanding the role which antigenic variation in pili play in the pathogenesis of Neisseria gonorrhoeae infections; again, using a human challenge model in collaboration with the STDCRC in Chapel Hill, NC. Three projects focus on different aspects of human papillomavirus (HPV) infections. One of these is directed at the mechanisms by which the E7 gene product of high risk HPV contributes to the development of anogenital malignancies and the pathogenesis of infection. The second seeks to define the extent to which immunosuppression associated with transplantation or pregnancy results in reactivation and expression of latent HPV infection; while a third project is focused on the mechanisms by which gene expression and replication of HPV are regulated by silencer and other genetic elements. Consistent with the objective of primary prevention is a project which seeks to define the timing of recurrent sexually transmitted infections and their relationship to inter- and intra-personal factors which may modify the risk of recurrent infection. These seven projects will be supported by an Administrative Core, a Biostatistical Core, and a Clinical/Laboratory Core with the latter monitoring sexually transmitted diseases as biological markers for evidence of recurrent infection. This core will also collect specimens and data from individuals infected with the different sexually transmitted pathogens and distribute them, along with appropriate clinical data, to the various projects. The extensive collaboration and cross- disciplinary fertilization which exists among the different projects will be reinforced by frequent scientific/administrative meetings to assess progress of each project and provide constructive criticism and assistance.